Chronic ethanol ingestion impairs alveolar type II cell glutathione homeostasis and function and predisposes to endotoxin-mediated acute edematous lung injury in rats.
Chronic alcohol abuse increases the incidence and mortality of the acute respiratory distress syndrome (ARDS) in septic patients. To examine a potential mechanism, we hypothesized that ethanol ingestion predisposes to sepsis-mediated acute lung injury by decreasing alveolar type II cell glutathione homeostasis and function. Lungs isolated from rats fed ethanol (20% in water for >/= 3 wk), compared with lungs from control-fed rats, had greater (P < 0. 05) edematous injury (reflected by nonhydrostatic weight gain) after endotoxin (2 mg/kg intraperitoneally) and subsequent perfusion ex vivo with n-formylmethionylleucylphenylalanine (fMLP, 10(-7) M). Ethanol ingestion decreased (P < 0.05) glutathione levels in the plasma, lung tissue, and lung lavage fluid, and increased (P < 0.05) oxidized glutathione levels in the lung lavage fluid. Furthermore, ethanol ingestion decreased type II cell glutathione content by 95% (P < 0.05), decreased (P < 0.05) type II cell surfactant synthesis and secretion, and decreased (P < 0.05) type II cell viability, in vitro. Finally, treatment with the glutathione precursors S-adenosyl-L-methionine and N-acetylcysteine in the final week of ethanol ingestion significantly reduced lung edema during perfusion ex vivo. We conclude that ethanol ingestion in rats alters alveolar type II cell glutathione levels and function, thereby predisposing the lung to acute edematous injury after endotoxemia. We speculate that chronic alcohol abuse in humans predisposes to ARDS through similar mechanisms.
Holguin
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F
Atlanta VAMC and the Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30033, USA.
Moss
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I
Brown
L A
LA
Guidot
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DM
D000111:Acetylcysteine / Q000494:pharmacology; D000208:Acute Disease; D000428:Alcohol Drinking; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015984:Causality; D002470:Cell Survival; D010478:Chemotherapy, Cancer, Regional Perfusion; D004731:Endotoxins / Q000494:pharmacology*; D000431:Ethanol / Q000008:administration & dosage* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006706:Homeostasis; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D055370:Lung Injury; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000096:biosynthesis / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012436:S-Adenosylmethionine / Q000494:pharmacology
D001427:Bacterial Toxins; D004731:Endotoxins; D010713:Phosphatidylcholines; D011663:Pulmonary Surfactants; C017463:lecithins, disaturated; C027952:salmonella toxin; D000431:Ethanol; D009240:N-Formylmethionine Leucyl-Phenylalanine; D012436:S-Adenosylmethionine; D005978:Glutathione; D000111:Acetylcysteine